Field of the Invention
The present disclosure relates to orthomolecular compositions comprising multiple phytochemical active ingredients, and pharmaceutical formulations thereof. In particular aspects, the disclosure is directed to compounding a plurality of active ingredients to produce a multi-component formulation that has both potent anti-inflammatory capabilities and the ability to inhibit aberrant tissue renin-angiotensin factors (tRAS). In related embodiments, the present disclosure provides prophylactic and therapeutic methods for use in affected or at-risk mammalian (and particularly, human) subjects, a) to stabilize the extracellular matrix (ECM); b) to prevent, treat, or ameliorate one or more symptoms of acute or chronic disease; and c) to prevent, alter, or modulate acute and/or chronic aberrant biological activities, including, for example, those attributable to tRAS peptides, enzymes, and receptors, or overexpression of the oxidoreductases, COX-2 and LOX.
Description of Related Art
Breast Carcinoma
Disease of the breast is currently rising in the American population at an alarming rate. Fibrocystic changes, fibroadenomas, and breast cancer have even been termed by some as reaching “epidemic” proportion. Statistics show that breast cancer is the second leading cause of death in women ages 20-59. In the United States, a new breast cancer is diagnosed every 3 minutes, with approximately 63,000 new cases of carcinoma in situ (CIS) being reported annually. The incidence of ductal CIS (DCIS) rose from 1.87 per 100,000 in 1973-1975 to approximately 32.5 per 100,000 in 2004. Alarmingly, over 40,000 women die from breast cancer on a yearly basis. Unfortunately, for those with advanced forms of the disease, chemotherapy has not significantly affected long-term survival rates.
Prevention of breast cancer, or any cancer for that matter, has been an elusive goal especially when employing the current medical paradigm. Since the Nixon administration declared “war on cancer” in the 1970s, a great deal of research and money has been devoted to achieving this end. Unfortunately, the battle remains un-won, despite valiant efforts across both research and treatment fronts. In spite of the many billion dollars allocated for this “war,” relatively little progress has been made, particularly in its prevention or in increasing the long-term survivability of those with advanced metastatic disease. Although many (and oftentimes, expensive) chemotherapeutic agents are at the physician's disposal, the ultimate solution for winning the battle with cancer still eludes even the brightest contemporary minds. Currently there is only a 2.3% increase in survival rate using chemotherapy.
The failure to win the war, however, is not from lack of resource allocation, but a faulty plan-of-attack based solely on the prevailing paradigm of intervention at the cellular level. Medicine's current view of early carcinogenesis focuses on the relationship of the cell as the driving force behind the neoplastic process. This has been termed as the “somatic mutation theory” or SMT, which argues that an accumulation of mutations and other heritable changes in the susceptible cell can result in cancer. The SMT paradigm, however, is not without its critics. Problems with its basic tenets have been noted in a number of scientific publications by Kolata, Sonnenschein, Soto, and other well-known artisans in the field.
The inventors have noticed various observations, however, that question the validity of the SMT paradigm. These observations include, for example: 1) mice fitted with subcutaneous filters that have small holes give rise to tumor formation while mice fitted with the same filter material but having only larger holes remained tumor-free; 2) transplantation of normal rat mammary cells into adjacent stroma (which was cleared of local epithelia cells but previously exposed to a chemical carcinogen) results in a much higher tumor rate as compared to controls; and 3) transplantation of normal cells into untreated, but “inappropriate,” stromal environment induced carcinoma formation. Yet, these now-abnormal cells returned to a normal state upon transplantation back into their original “appropriate” stromal environment.
The Extracellular Matrix (ECM)
In cell biology, the term “extracellular matrix” (ECM) refers to the extracellular part of animal tissue that provides structural support to the cells, and performs various other important functions. ECM is the defining feature of connective tissue in animals, and includes the interstitial matrix (present in the intracellular spaces around various animal cells) and the basement membrane (sheet-like depositions of ECM on which various epithelial cells rest). It provides support and anchorage for cells, sequesters cellular growth factors, regulates intercellular communication, and segregates or compartmentalizes various types of cells that are contained within the matrix.
The interstitial space is composed of a number of biological molecules, including, glycosaminoglycans (GAG) and fibrous proteins that form an interlocking mesh that act as a compression buffer against the stress placed on the ECM. Glycosaminoglycans consist of repeating disaccharide units. Hyaluronan (HA) lacks any sulfate groups, but the rest of the GAGs contain sulfates at various positions.
Formation of ECM is essential for processes like cell growth, tissue differentiation, wound healing and fibrosis. An understanding of the complex structure and function of the ECM also helps facilitate analysis of the dynamics of tumor invasion and cancer metastasis, which often involve destruction of ECM by matrix metalloproteinases and serine and threonine proteases.
Components of the ECM are produced intracellularly by resident cells, and secreted into the ECM via exocytosis. Once secreted, they then aggregate with the existing matrix. As described by Varki et al. (1999), the ECM determines the physical characteristics of tissues and many of the biological properties of cells embedded in it. Major components of the ECM are fibrous proteins that provide tensile strength (e.g., various collagens and elastin), adhesive glycoproteins (e.g., fibronectin, laminin, elastin, and tenascin), and proteoglycans that provide a hydrated gel that resists compressive forces.
Proteoglycans consist of a core protein and one or more covalently attached GAG chains. GAGs are linear polysaccharides, whose building blocks (disaccharides) consist of an amino sugar (either GlcNAc or GalNAc) and uronic acid (GlcA and IdoA). Virtually all mammalian cells produce proteoglycans and either secrete them into the ECM, insert them into the plasma membrane, or store them in secretory granules. The matrix proteoglycans include small interstitial proteoglycans (e.g., decorin, biglycan, and fibromodulin), a proteoglycan form of type IX collagen, and one or more members of the aggrecan family of proteoglycans (e.g., aggrecan, brevican, neurocan, and versican). Some of these proteoglycans contain only one GAG chain (e.g., decorin), whereas others have more than 100 chains (e.g., aggrecan). The matrix proteoglycans typically contain the GAGs known as chondroitin sulfate (CS) or dermatan sulfate (DS). Exceptions to this generalization exist, since the heparan sulfate (HS) proteoglycans, perlecan and agrin, are major species found in basement membranes. A number of different types of proteoglycans are also found within the ECM, including keratin sulfate.
Disruption of the ECM in animal tissues has been implicated in a number of disease processes. ECM deterioration has been associated with poor prognosis of many types of connective and hyperproliferative disorders. In particular, destabilization of proper ECM structure and function in human tissues such as breast and prostate tissues has been shown to aggravate the disease process in those organs. This disruption manifests itself in a number of indications, including overexpression of tRAS, inflammation, infection, loss of tissue integrity and biochemical imbalances in the cells contained within the matrix, and can lead to increases in mammographic density, microcalcification, degeneration of healthy tissue, and a number of neoplastic and other disease processes in situ. Accordingly, there is a need in the art for compositions that improve the health of ECM-rich mammalian tissues, limit ECM deterioration and dysfunction, increase stabilization of the ECM and its resident cellular cooperative, and reduce, eliminate, or prevent harmful cellular processes such as aberrant tRAS angiogenesis, inflammation, microcalcification, and the development of neoplastic disease.